Nasr T.Bondock S.Rashed H.M.Fayad W.Youns M.Sakr T.M.Department of Pharmaceutical ChemistryFaculty of PharmacyHelwan UniversityEgypt; Department of Pharmaceutical ChemistryFaculty of PharmacyModern University for Technology and InformationEgypt; Department of ChemistryFaculty of ScienceMansoura UniversityMansouraET-35516Egypt; Department of ChemistryFaculty of ScienceKing Khalid UniversityAbha9004Saudi Arabia; Labeled Compounds DepartmentHot Labs CenterEgyptian Atomic Energy AuthorityP.O. Code 13759CairoEgypt; Drug Bioassay-Cell Culture LaboratoryPharmacognosy DepartmentNational Research CentreDokkiGiza 12622Egypt; Department of Biochemistry and Molecularlar BiologyFaculty of PharmacyHelwan UniversityEgypt; Radioactive Isotopes and Generators DepartmentHot Laboratories CentreAtomic Energy AuthorityP.O. Code 13759CairoEgypt; Pharmaceutical Chemistry DepartmentFaculty of PharmacyOctober University of Modern Sciences and Arts (MSA)GizaEgypt2020-01-092020-01-0920182235234https://doi.org/10.1016/j.ejmech.2018.04.014PubMed ID 29665526https://t.ly/52MAYScopusMSA Google ScholarThe current work presents the synthesis and biological evaluation of new series of coumarin hydrazide-hydrazone derivatives that showed in vitro broad spectrum antitumor activities against resistant pancreatic carcinoma (Panc-1), hepatocellular carcinoma (HepG2) and leukemia (CCRF) cell lines using doxorubicin as reference standard. Bromocoumarin hydrazide-hydrazone derivative (BCHHD) 11b showed excellent anticancer activity against all tested cancer cell lines. Enzyme assays showed that BCHHD 11b induced apoptosis due to activation of caspases 3/7. Moreover, 11b inhibited GST and CYP3A4 in a dose dependent manner and the induced cell death could be attributed to metabolic inhibition. Moreover, 11b microarray analysis showed significant up- and down-regulation of many genes in the treated cells related to apoptosis, cell cycle, tumor growth and suppressor genes. All of the above presents BCHHD 11b as a potent anticancer agent able to overcome drug resistance. In addition, compound 11b was able to serve as a chemical carrier for 99mTc and the in vivo biodistribution study of 99mTc-11b complex revealed a remarkable targeting ability of 99mTc into solid tumor showing that 99mTc-11b might be used as a promising radiopharmaceutical imaging agent for cancer. � 2018 Elsevier Masson SASEnglishOctober University for Modern Sciences and Artsجامعة أكتوبر للعلوم الحديثة والآدابUniversity of Modern Sciences and ArtsMSA UniversityApoptosisCaspases 3/7Coumarin hydrazide-hydrazoneCYP3A4GSTMicroarrayRadiolabeling2 chloro 6 ethoxy 3 formylquinoline2 oxo n' [(pyridin 3 yl)methylene] 2h chromene 3 carbohydrazide2 oxo n' [(pyridin 4 yl)methylene] 2h chromene 3 carbohydrazide6 bromo 2 oxo n' [(pyridin 3 yl)methylene] 2h chromene 3 carbohydrazide6 bromo 2 oxo n' [(pyridin 4 yl)methylene] 2h chromene 3 carbohydrazide6 bromo n (4 ethoxyphenyl) 2 oxo 2h chromene 3 carboxamide6 bromo n' [(2 chloro 6 ethoxyquinolin 3 yl)methylene] 2 oxo 2h chromene 3 carbohydrazide6 nitro 2 oxo n' [(pyridin 3 yl)methylene] 2h chromene 3 carbohydrazide6 nitro 2 oxo n' [(pyridin 4 yl)methylene] 2h chromene 3 carbohydrazide7 hydroxy 2 oxo n' [(pyridin 3 yl)methylene] 2h chromene 3 carbohydrazideamideantineoplastic agentcaspase 3caspase 7coumarin derivativecytochrome P450 3A4doxorubicinhydrazide derivativehydrazone derivativen (4 ethoxyphenyl) 2 oxo 2h chromene 3 carboxamiden (4 ethoxyphenyl) 6 nitro 2 oxo 2h chromene 3 carboxamiden (4 ethoxyphenyl) 7 hydroxy 2 oxo 2h chromene 3 carboxamiden (4 {[(3,4 dimethylisoxazol 4 yl)amino]sulfonyl}phenyl) 2 oxo chromene 3 carboxamiden (4 {[(3,4 dimethylisoxazol 4 yl)amino]sulfonyl}phenyl) 6 bromo 2 oxo chromene 3 carboxamiden (4 {[(3,4 dimethylisoxazol 4 yl)amino]sulfonyl}phenyl) 6 nitro 2 oxo chromene 3 carboxamiden' [(2 chloro 6 ethoxyquinolin 3 yl)methylene] 2 cyanoacetohydraziden' [(2 chloro 6 ethoxyquinolin 3 yl)methylene] 2 oxo 2h chromene 3 carbohydraziden' [(2 chloro 6 ethoxyquinolin 3 yl)methylene] 6 nitro 2 oxo 2h chromene 3 carbohydraziden' [(2 chloro 6 ethoxyquinolin 3 yl)methylene] 7 hydroxy 2 oxo 2h chromene 3 carbohydrazideunclassified drugunindexed drugantineoplastic agentcoumarin derivativecytochrome P450 3Acytochrome P450 3A inhibitorhydrazone derivativeantiproliferative activityapoptosisArticlecell cyclecontrolled studydown regulationdrug bioavailabilitydrug cytotoxicitydrug screeningdrug synthesisenzyme activationenzyme assayHep-G2 cell linehumanhuman cellin vitro studyin vivo studyisotope labelingKnoevenagel condensationleukemialiver cell carcinomametabolic inhibitionmicroarray analysisPANC-1 cell linepancreas carcinomapharmacokinetic parametersproton nuclear magnetic resonancestructure activity relationtumor growthtumor suppressor geneupregulationanimalchemistrydrug effecthalogenationmetabolismmouseneoplasmpathologysynthesistissue distributiontumor cell lineAnimalsAntineoplastic AgentsApoptosisCell Line, TumorCoumarinsCytochrome P-450 CYP3ACytochrome P-450 CYP3A InhibitorsHalogenationHumansHydrazonesMiceNeoplasmsTissue DistributionArticlehttps://doi.org/10.1016/j.ejmech.2018.04.014PubMed ID 29665526